NVALT28/ PRL01: Durvalumab and low-dose Prophylactic Cranial Irradiation (PCI) versus durvalumab and observation in radically treated patients with stage III non-small cell lung cancer: A phase III randomized study

The brain is frequently a site of disease relapse in Non-Small Cell Lung Cancer
(NSCLC) patients. Therapy with curative intent for (symptomatic) brain
metastases is seldom possible and for the overwhelming majority of patients
with brain metastases it is impossible to obtain long-term survival. Therefore,
strategies to reduce incidence of brain metastases are necessary. It has
already been shown that the type of chemotherapy used during chemoradiation
does not influence the incidence of brain metastases.
Prophylactic Cranial Irradiation (PCI) has been shown to reduce the incidence
of brain metastases in patients with NSCLC. Thus far, no effect of PCI on
Overall Survival (OS) has been demonstrated, but in three phase III studies,
including our own NVALT-11/DLCRG-02 study, the Progression-Free Survival (PFS)
after 2 years and longer improved in the PCI group. PCI leads to a
neuro-cognitive impairment in about 25% of patients without altering the Qo,
mostly grade 1-2.
The PACIFIC study showed that with the addition of durvalumab after
chemo-radiotherapy in stage III NSCLC, the incidence of brain metastases could
be reduced by 50%, i.e. from approximately 12% to 6%. The median follow-up in
the updated analysis of this trial was 25.2 months. The percentage brain
metastases in the control arm was surprisingly low, as all other trials with a
similar control arm had a percentage of brain metastases that was at least
twice as high. Durvalumab was generally well tolerated.
In pre-clinical models, immunotherapy potentiates the effects of radiotherapy
by a factor two to five. This makes the combination of PCI and immunotherapy
interesting to evaluate whether it can further decrease the percentage of brain
metastases as well as preserve organ function as a lower radiation dose can
probably be used when combined with an anti-programmed death (ligand)1
(PD(L)-1).
We therefore hypothesize that the combination of PCI with durvalumab will
decrease the incidence of brain metastases from 30% (as in all phase III trials
designed for this purpose) to 15 % with durvalumab and to a maximum of 5% with
the addition of low-dose PCI. This strategy would make brain metastases in
stage III NSCLC history and this would improve QoL.

To evaluate whether the addition of PCI to durvalumab after concurrent
chemo-radiotherapy for stage III NSCLC reduces the cumulative incidence of
brain metasta-ses

This is an open-label, 1:1 randomized phase III trial.

PCI or no PCI. PCI will be given to a dose of 15 Gy in 10 fractions (i.e. half
of the dose normally given because of the anticipated radiosensitizing effect
of durvalumab). PCI with sparing of the hippocampi (HA-PCI) is not mandatory
but is allowed. PCI has to start within 62 days after the last dose of thoracic
radiotherapy. The Hopkins Verbal Learning Test Revised - total recall score
test will be used to assess learning. Optionally, quality of life (EORTC
QLQ-C30, EORTC Euroqol 5D and PRO-CTCAE) will be measured, and optionally,
additional neurocognitive functioning tests will be performed with the
Amsterdam Cognition Scan test battery.
Blood as well as imaging will be collected for translational purposes and to
study cardiac toxicity. The tumor biopsy performed at initial stage III NSCLC
diagnosis will also be collected for translational purposes.
Moreover, baseline and 6-monthly ECG and cardiac markers (all up to 5 years)
will be obtained (BNP, troponin), as cardiotoxicity of chemoradiation followed
by durvalumab is not well studied. Patients may be referred to a cardiologist
when cardiac evaluations are abnormal.

Adjuvant durvalumab showed a favorable toxicity profile in the PACIFIC trial
(adjuvant durvalumab after concurrent chemoradiation for stage III NSCLC). Only
a slight increase in pneumonitis was seen compared to placebo, but most of
these were low grade. In the same trial, durvalumab improved PFS and OS and
time to distant metastases (including brain me-tastases) compared to placebo.
PCI decreases the risk of brain metastases by approximately 50%. In the NVALT
11/DLCRG-02 trial (inclusion from 2009 till 2015), no decrease in QoL was seen
with PCI compared to observation. In the RTOG0214 trial, PCI resulted in a
decline in memory after 1 year, but without a decline in QoL or Mini mental
State Examination MMSE test (but MMSE is only suitable to detect major
cognitive impairments).

The HVLT-R takes 5-10 minutes to complete, with 20 minutes interval, and will
be done at screening, 4 months after randomization and then yearly up to year
5. The test is not emotionally disturbing. The HVLT-R has to be performed on
paper. The HVLT-R will be administered together with other cognitive tests from
the Amsterdam Cognition Scan (the Amsterdam Cognition Scan [ACS] is optional).
Time for completing the ACS is 40 minutes (including two short fixed breaks),
The ACS is currently running in ten clinical oncology trials. Patients do not
consider the ACS as burdensome and they appreciate the ease and efficiency of
completing these tests from home.
The questionnaires used in this trial are not burdensome and are also optional,
time to complete the questionnaires is maximum 20 minutes for the QLQ-C30 and
EuroQol 5D, and is 5minutes for PRO-CTCAE.

Tumour assessments (CT-thorax and upper abdomen) are at randomization and
thereafter every 6 months for the first 2 years. After these 2 years, CT-thorax
and upper abdomen will be performed yearly, and then the last imaging
(CT-thorax and upper abdomen, MRI brain) 5 years after randomization. The
frequency of CT is similar to standard of care.
MRI brains will be performed every 6 months up to 5 years after randomization.
MRI brain during staging for stage III NSCLC is standard of care, the other
MRIs are additional. Time per MRI is approximately 30 minutes. The MRI is
non-invasive except for a venepuncture to administer gadolinium-contrast for
the MRI. The risks of a MRI-scan are negligible because it is a magnetic field
and does not involve ionizing radiation. The venepuncture can cause a hematoma.
Blood draws are part of standard of care to check whether durvalumab can be
safely administered (i.e. each cycle of durvalumab, and during follow-up).
Additional blood samples will only be drawn when a regular sample is scheduled,
thus avoiding an additional burden for the patient.
ECG before randomization and the other 6-monthy ECGs are additional (they are
performed up to year 5). ECGs are non-invasive and time per ECG is only 5-10
minutes.
A possible benefit for the patient is that ECGs are performed, and possible
cardiac abnormalities will be discovered in an earlier state. Patients may be
referred to a cardiologist when an ECG is abnormal.